Based on clinical findings and evidence from their relevant preclinical models, dysfunctional glutamate transmission has important roles in a variety of disease pathologies. In the progression of these diseases, the underlying mechanisms for glutamate's release and/or uptake significantly involve its intercellular transmission caused by abnormal intercellular ion flows through respective cellular membrane's ion channels. As indicated below, the modulation (e.g., blockade) of these channels by published drugs (either directly, or via inducing a cascade of intervening pathways) can attenuate such disease progression.
Many neurological and psychiatric diseases involve dysfunctional glutamate transmission caused by abnormal Na and/or Ca activated K (also known as KCa2, SK) ion channels—(e.g., A. Doble, The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy, Pharmacol. Ther. Vol. 81 (3), pp. 163-221 and J. Lam, et. al. The Therapeutic Potential of Small-Conductance KCa2 Channels in Neurodegenerative and Psychiatric Diseases, Expert Opin Ther Targets Vol. 17(10), pp. 1203-1220). Such neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), chronic pain such as neuropathy, multiple sclerosis (MS), ataxia, Parkinson's disease, Huntington's disease, Tourette syndrome, epilepsy, dystonia, Fragile X syndrome and disorders resulting from traumatic brain/spinal cord injuries or from cerebral ischemia. Psychiatric diseases include depression, anxiety, bipolar disorder, schizophrenia, obsessive compulsive disorder, autism, glaucoma induced optical neuropathy and alcohol/drug addiction. Cognitive dysfunctions include but not limited to dementia (vascular and Alzheimer's disease) and attention deficit/hyperactive disorder (ADHD). Unfortunately when the above mentioned diseases/disorders are progressive, they resist currently approved drug therapies at late stages or become resistant after starting drug therapies at earlier stages. For example in major depression, significant patient populations (10-55% depending on the database accessed) are/become ‘treatment resistant’. In epilepsy, a significant minority (20-30%) of patients are/become resistant to currently approved drugs. Epilepsy, a complex neurological disorder estimated to affect over 50 million people worldwide, is characterized by recurrent spontaneous seizures due to neuronal hyperexcitability and hypersynchronous neural firing. Despite the availability of more than 20 antiepileptic drugs (AEDs), 30% of patients with epilepsy continue to experience seizures or suffer from undesirable drug side effects such as drowsiness, behavior changes, liver damage or teratogenicity.
In addition, the glutamate uptake involving tumor cell's Na-receptor channels is believed to potentiate cancer metastasis (e.g., M. B. A. Djamgoz, Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease, Recent Pat Anticancer Drug Discov. Vol. 8(1), pp. 66-84 and T. Koltai, Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs, F1000 Research Vol. 4, p. 297). In a Phase 2 clinical trial of patients having metastatic melanoma and then treated with Riluzole (for which the current marketing approval is only to treat ALS. In the clinical trial, metastasis was initially stabilized in 42% despite no overall improvement of RECIST grade. To further improve Riluzole's efficacy to treat metastatic melanoma, a combination therapy with other anticancer drugs was proposed.
Therefore, novel drugs are urgently needed to treat these ‘resistant’ patients whether as monotherapy or integrated into combination regimens (e.g., some combinations of existing drugs to treat epilepsy: N. Matsumura, Isobolographic analysis of the mechanisms of action of anticonvulsants from a combination effect, European Journal of Pharmacology, Vol. 741, pp. 237-246).
The compounds and pharmaceutical formulations disclosed in the present application are believed to be effective in providing the needed solution of achieving modulation of dysfunctional glutamate transmission for the aforementioned therapeutic indications.